In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a leading cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents that are currently in use include .beta..sub.2 -adrenergic agonists, magnesium sulfate and ethanol. Ritodrine, the leading .beta..sub.2 -adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other .beta..sub.2 -adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuro-muscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
Selective I.sub.Ks modulators are presented which are ideal tocolytic agents. The I.sub.sK or minK channel gene has been cloned from diethylstibestrol (DES)--primed uterine tissue and its expression in Xenopus occytes results in a slowly activating potassium current that resembles the I.sub.Ks current constituitively expressed in mammalian cardiac cells. (Boyle et al., Science 235:1221-1224, 1987; Boyle et al., Nature 330:373-375, 1987; Folander et al., Proc. Nat'l. Acad. Sci. 87:2975-2979, 1990; Sanguanetti and Jurkiewicz, J. Gen. Physiol., 96;195-215, 1990). Northern analysis demonstrates that the I.sub.sK gene which encodes for a sub-unit of the channel that underlies the I.sub.Ks current, is expressed in DES-primed uterine tissue. (Folander et al., Proc. Natl. Acad. Sci. 87:2975-2979, 1990). Uterine contraction is associated with and triggered by prolonged bursts of action potentials which occur as a result of the depolarization of smooth muscle. (Kuriyama and Suzuki., J. Physiol. (London) 260:315--et seq., 1976). Therefore, activation of I.sub.sK, resulting in membrane hyperpolarization should prevent or inhibit the maintained depolarization and bursting of action potentials and thereby inhibit smooth muscle contraction and/or promote smooth muscle relaxation.
In the instant invention, highly selective activators or agonists of I.sub.Ks current or I.sub.sK channel have been identified and characterized. These compounds which promote opening of the I.sub.sK channel allow effux of positively charged potassium ions (K.sup.+) ions to flow out or exit cells through the cell membrane which produces a hyperpolarization of the transmembrane voltage gradient. This hyper-polarization will prevent or inhibit contraction of excitable smooth muscle cells of the uterus which occur as a direct consequence of membrane depolarization. The inhibition of smooth muscle contraction is beneficial in the treatment of preterm labor or premature uterine contraction.
The method of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By modulating the IKs current in the uterus, selective, more efficacious treatment of dysmenorrhea will result. An additional use for the present invention is for the stoppage of labor preparatory to vaginal or Cesarean delivery.
It is, therefore, a purpose of this invention to provide a method of treatment which more effectively modulates the IKs current in disease states in animals, preferably mammals, especially in humans. It is still another purpose of this invention to provide a method of modulating the IKs current in disease states in mammals. It is also a purpose of this invention to develop a method of preventing or treating disorders of preterm labor and dysmenorrhea by modulating I.sub.Ks current.
It has now been found that compounds of the present invention are modulators of IKs current. When the IKs current is modulated by the compounds of the present invention, the IKs channel is activated and exerts its biologic or pharmacologic effects. This method is useful in the treatment and prevention of certain gynecological and obstetrical disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. This method would also find usefulness for stoppage of labor preparatory to vaginal or Cesarean delivery.